In prior work, we have pursued how tumor reactive monoclonal antibody (mAb), together with activators of innate immune cells, like NK cells, can augment antibody dependent cell-mediated cytotoxicity (ADCC) of cancer cells in vitro. Following preclinical development in mice, this work has been translated into clinical efficacy in the setting of maintenance therapy for high risk neuroblastoma, and the FDA approval of the anti-GD2 mAb, dinutuximab. We have shown how the genotype of patients for NK inhibitory KIR genes can influence the activity of this therapy. More recently, we have identified a novel combination therapy (“In Situ Vaccination”) given directly to a large existing tumor that enables it to function as a potent vaccine, providing long-lasting cure of mice from large tumors that were previously non-curable with other immunotherapy approaches. Following local radiotherapy (RT), we directly inject a tumor-reactive immunocytokine [a tumor-reactive anti-GD2 mAb linked to IL2, a potent immune cell activator]. Most mice bearing a single large melanoma show tumor elimination with long lasting protective immunity with this approach (Morris et al, Cancer Research, 76:3929, 2016). In mice with 2 tumors, delivering RT to both the 1st + 2nd tumors, or adding checkpoint-blockade therapy using an anti-CTLA-4 mAb, enables injection of immunocytokine to the 1st tumor to eradicate it as well as the 2nd tumor in most mice. (Morris et al, Cancer Immunology Research,6: 825-834, 2018). Clinical testing in melanoma is being initiated. Preliminary results are similar in mice bearing pancreatic cancer or neuroblastoma, and clinical translation in neuroblastoma has been started. We hypothesize that In Situ Vaccination will also be effective in other tumors that appear resistant to checkpoint-blockade.
1. Immune responses can be induced against “cold” tumors
2. Combined approaches, activating presentation and recognition, blocking an immunosuppressive micro-environment, and “taking off the brakes” can be synergistic.